Does nonlinear blood-brain barrier transport matter for (lower) morphine dosing strategies?

Morphine blood-brain barrier (BBB) transport is governed by passive diffusion, active efflux and saturable active influx. This may result in nonlinear plasma concentration-dependent brain extracellular fluid (brainECF) pharmacokinetics of morphine. In this study, we aim to evaluate the impact of nonlinear BBB transport on brainECF pharmacokinetics of morphine and its metabolites for different dosing strategies using a physiologically based pharmacokinetic simulation study. We extended the human physiologically based pharmacokinetic LeiCNS-PK3.0, model with equations for nonlinear BBB transport of morphine. Simulations for brainECF pharmacokinetics were performed for various dosing strategies: intravenous (IV), oral immediate (IR) and extended release (ER) with dose range of 0.25-150 mg and dosing frequencies of 1-6 times daily. The impact of nonlinear BBB transport on morphine CNS pharmacokinetics was evaluated by quantifying (i) the relative brainECF to plasma exposure (AUCu,brainECF/AUCu,plasma) and (ii) the impact on the peak-to-trough ratio (PTR) of concentration-time profiles in brainECF and plasma. We found that the relative morphine exposure and PTRs are dose dependent for the evaluated dose range. The highest relative morphine exposure value of 1.4 was found for once daily 0.25 mg ER and lowest of 0.1 for 6-daily 150 mg IV dosing. At lower doses the PTRs were smaller and increased with increasing dose and stabilized at higher doses independent of dosing frequency. Relative peak concentrations of morphine in relation to its metabolites changed with increasing dose. We conclude that nonlinearity of morphine BBB transport affects the relative brainECF exposure and the fluctuation of morphine and its metabolites mainly at lower dosing regimens.

Recurrence rate of basal cell carcinoma among different micrographic surgery techniques: systematic review with meta-analysis.

In high-risk basal cell carcinomas (BCCs), micrographic surgery (MS) has high tissue preservation and low recurrence rates. The Mohs technique is the most commonly used technique, with limited use of other MS techniques. No studies have been designed to compare the MS methods. This review aimed to assess BCC recurrence rates of different MS techniques. A systematic review and meta-analysis were conducted to search for related studies in PubMed, LILACS, EMBASE, SCOPUS, WEB OF SCIENCE, CINHAL and COCHRANE until March 2021. Randomized clinical trials (RCTs) and observational studies involving patients with BCC and indications for different MS techniques were included. Study selection and data extraction were performed independently by three peer reviewers, as was the risk of bias assessment using the Joanna Briggs Institute tool. Pooled estimates were assessed using the random-effects model (Logit), and heterogeneity was assessed by the chi-squared test (χ2 ). Stata Software version 17.0 was used for analysis. Eighteen studies were included, two RCTs and sixteen observational studies. The overall recurrence rate was 2% (95% CI, 1.0-3.0%; χ2 = 46.2; P = 0.00; 18 studies, 10 424 BCCs). In studies using the Mohs technique, the recurrence rate was 3.0% (95% CI, 1.0-5.0%; χ2 = 11.0; P = 0.00; 6 studies; 1,582 BCCs), with the Munich technique 3.0% (95% CI, 2.0-5.0%; χ2 = 0.0; no heterogeneity; 3 studies; 404 BCCs), with Tubingen technique 1% (95% CI, 1.0-2.0%; χ2 = 12.1; P = 0.00; 8 studies; 8374 BCCs) and with the Muffin technique 0.0% (95% CI, 0.0-6.0%; 1 study; 64 BCCs). Relapse rates between MS techniques were low and appeared to be similar. However, the design of this review and the absence of primary studies that directly compare the techniques do not allow us to assert the superiority between them.

Patient's thoughts and expectations about centres of expertise for PKU.

BACKGROUND: In the Netherlands (NL) the government assigned 2 hospitals as centres of expertise (CE) for Phenylketonuria (PKU), while in the United Kingdom (UK) and Germany no centres are assigned specifically as PKU CE's. METHODS: To identify expectations of patients/caregivers with PKU of CEs, a web-based survey was distributed through the national Phenylketonuria societies of Germany, NL and UK. RESULTS: In total, 105 responded (43 patients, 56 parents, 4 grandparents, 2 other) of whom 59 were from NL, 33 from UK and 13 from Germany. All participants (n = 105) agreed that patients and/or practitioners would benefit from CEs. The frequency patients would want to visit a CE, when not treated in a CE (n = 83) varied: every hospital visit (24%, n = 20), annual or bi-annual (45%, n = 37), at defined patient ages (6%, n = 5), one visit only (22%, n = 18), or never (4%, n = 3). Distance was reported as a major barrier (42%, n = 35). 78% (n = 65) expected CE physicians and dieticians to have a higher level of knowledge than in non-CE centres. For participants already treated in a CE (n = 68), 66% requested a more extensive annual or bi-annual review. In general, psychology review and neuropsychologist assessment were identified as necessary by approximately half of the 105 participants. In addition, 66% (n = 68) expected a strong collaboration with patient associations. CONCLUSION: In this small study, most participants expected that assigning CEs will change the structure of and delivery of Phenylketonuria care.

Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials.

Richter transformation (RT) is defined as development of aggressive lymphoma in patients (pts) with CLL. The incidence rates of RT among pts with CLL range from 2 to 10%. The aim of this analysis is to report the frequency, characteristics and outcomes of pts with RT enrolled in trials of the GCLLSG. A total of 2975 pts with advanced CLL were reviewed for incidence of RT. Clinical, laboratory, and genetic data were pooled. Time-to-event data, starting from time of CLL diagnosis, of first-line therapy or of RT diagnosis, were analyzed by Kaplan-Meier methodology. One hundred and three pts developed RT (3%): 95 pts diffuse large B-cell lymphoma (92%) and eight pts Hodgkin lymphoma (8%). Median observation time was 53 months (interquartile range 38.1-69.5). Median OS from initial CLL diagnosis for pts without RT was 167 months vs 71 months for pts with RT (HR 2.64, CI 2.09-3.33). Median OS after diagnosis of RT was 9 months. Forty-seven pts (46%) received CHOP-like regimens for RT treatment. Three pts subsequently underwent allogeneic and two pts autologous stem cell transplantation. Our findings show that within a large cohort of GCLLSG trial participants, 3% of the pts developed RT after receiving first-line chemo- or chemoimmunotherapy. This dataset confirms the ongoing poor prognosis and high mortality associated with RT.

Randomized phase-II trial evaluating induction therapy with idarubicin and etoposide plus sequential or concurrent azacitidine and maintenance therapy with azacitidine.

The aim of this randomized phase-II study was to evaluate the effect of substituting cytarabine by azacitidine in intensive induction therapy of patients with acute myeloid leukemia (AML). Patients were randomized to four induction schedules for two cycles: STANDARD (idarubicin, cytarabine, etoposide); and azacitidine given prior (PRIOR), concurrently (CONCURRENT), or after (AFTER) therapy with idarubicin and etoposide. Consolidation therapy consisted of allogeneic hematopoietic-cell transplantation or three courses of high-dose cytarabine followed by 2-year maintenance therapy with azacitidine in the azacitidine-arms. AML with CBFB-MYH11, RUNX1-RUNX1T1, mutated NPM1, and FLT3-ITD were excluded and accrued to genotype-specific trials. The primary end point was response to induction therapy. The statistical design was based on an optimal two-stage design applied for each arm separately. During the first stage, 104 patients (median age 62.6, range 18-82 years) were randomized; the study arms PRIOR and CONCURRENT were terminated early due to inefficacy. After randomization of 268 patients, all azacitidine-containing arms showed inferior response rates compared to STANDARD. Event-free and overall survival were significantly inferior in the azacitidine-containing arms compared to the standard arm (p < 0.001 and p = 0.03, respectively). The data from this trial do not support the substitution of cytarabine by azacitidine in intensive induction therapy.

Improving the Prediction of Local Drug Distribution Profiles in the Brain with a New 2D Mathematical Model.

The development of drugs that target the brain is very challenging. A quantitative understanding is needed of the complex processes that govern the concentration-time profile of a drug (pharmacokinetics) within the brain. So far, there are no studies on predicting the drug concentration within the brain that focus not only on the transport of drugs to the brain through the blood-brain barrier (BBB), but also on drug transport and binding within the brain. Here, we develop a new model for a 2D square brain tissue unit, consisting of brain extracellular fluid (ECF) that is surrounded by the brain capillaries. We describe the change in free drug concentration within the brain ECF, by a partial differential equation (PDE). To include drug binding, we couple this PDE to two ordinary differential equations that describe the concentration-time profile of drug bound to specific as well as non-specific binding sites that we assume to be evenly distributed over the brain ECF. The model boundary conditions reflect how free drug enters and leaves the brain ECF by passing the BBB, located at the level of the brain capillaries. We study the influence of parameter values for BBB permeability, brain ECF bulk flow, drug diffusion through the brain ECF and drug binding kinetics, on the concentration-time profiles of free and bound drug.

P-glycoprotein protein expression versus functionality at the blood-brain barrier using immunohistochemistry, microdialysis and mathematical modeling.

A proper understanding of P-gp mediated transport (functionality) at the blood-brain barrier (BBB) and beyond is needed to interpret, understand and predict pharmacokinetic (PK)- pharmacodynamic (PD) relationships of CNS drugs that are substrates of P-gp, especially since P-gp functionality may be different in different conditions. Often, P-gp expression is taken as a biomarker of transporter functionality. The aim of our study was to investigate whether brain capillary protein expression of P-gp is associated with changes in P-gp mediated drug efflux at the BBB. Status Epilepticus (SE) was induced by kainate in male rats. During 3-5 weeks post SE, hippocampal P-gp expression was determined using immunohistochemistry, while BBB P-gp functionality was assessed by microdialysis of quinidine, in absence and presence of the P-gp blocker tariquidar. The data were analyzed using Non-linear Mixed Effect Modeling implemented in NONMEM. Following SE, changes in brain capillary P-gp expression were observed. However, no relation between BBB P-gp protein expression and BBB P-gp mediated drug efflux was found. This warrants a critical view on the interpretation of reported changes in BBB P-gp expression as a biomarker of BBB P-gp functionality.

Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics.

INTRODUCTION: Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. Then, the authors discuss how pharmacometabolomics gives insight into system-wide pharmacological effects and why it is a promising method to study interspecies differences. Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges. Expert opinion: It is envisioned that PK/PD-metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species.

Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk.

ESSENTIALS: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. SUMMARY: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, ß = -25.9 mU mL-1 per minor allele; FVIIa-AT, ß = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, ß = 7.8 mU mL-1 per minor allele; FVIIa-AT, ß = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk.

Analgosedation in paediatric severe traumatic brain injury (TBI): practice, pitfalls and possibilities.

Analgosedation is a fundamental part of traumatic brain injury (TBI) treatment guidelines, encompassing both first and second tier supportive strategies. Worldwide analgosedation practices continue to be heterogeneous due to the low level of evidence in treatment guidelines (level III) and the choice of analgosedative drugs is made by the treating clinician. Current practice is thus empirical and may result in unfavourable (often hemodynamic) side effects. This article presents an overview of current analgosedation practices in the paediatric intensive care unit (PICU) and addresses pitfalls both in the short and long term. We discuss innovative (pre-)clinical research that can provide the framework for initiatives to improve our pharmacological understanding of analgesic and sedative drugs used in paediatric severe TBI and ultimately facilitate steps towards evidence-based and precision pharmacotherapy in this vulnerable patient group.

Association between gestational diabetes mellitus exposure and childhood adiposity is not substantially explained by offspring genetic risk of obesity.

AIM: To examine the extent to which offspring obesity-associated genetic risk explains the association between gestational diabetes mellitus and childhood adiposity. METHODS: We studied 282 children aged 7-12 years who were enrolled in the Exploring Perinatal Outcomes in Children Study. A genetic risk score for BMI was calculated as the count of 91 established BMI-raising risk alleles. Multivariable linear and logistic regression models were used to estimate associations between the offspring genetic risk score and exposure to gestational diabetes and childhood adiposity (BMI and waist circumference), adjusting for clinical and demographic covariates. The contribution of offspring genetic risk to associations between maternal gestational diabetes and childhood outcomes was estimated by comparing the regression coefficients for the gestational diabetes variable in models with and without the genetic risk score. RESULTS: The offspring BMI genetic risk score was associated with childhood BMI (P = 0.006) and waist circumference (P = 0.02), and marginally with gestational diabetes (P = 0.05). Offspring BMI genetic risk did not contribute significantly to associations between gestational diabetes and childhood BMI [7.7% (95% CI -3.3, 18.8)] or waist circumference [5.8% (95% CI -3.1, 14.8); P = 0.2 for both]. CONCLUSIONS: Offspring obesity genetic risk does not explain a significant proportion of the association between gestational diabetes exposure and childhood adiposity. The association between gestational diabetes and childhood adiposity is probably explained through alternative pathways, including direct intrauterine effects or a shared postnatal environment.

Multivariate pharmacokinetic/pharmacodynamic (PKPD) analysis with metabolomics shows multiple effects of remoxipride in rats.

The study of central nervous system (CNS) pharmacology is limited by a lack of drug effect biomarkers. Pharmacometabolomics is a promising new tool to identify multiple molecular responses upon drug treatment. However, the pharmacodynamics is typically not evaluated in metabolomics studies, although being important properties of biomarkers. In this study we integrated pharmacometabolomics with pharmacokinetic/pharmacodynamic (PKPD) modeling to identify and quantify the multiple endogenous metabolite dose-response relations for the dopamine D2 antagonist remoxipride. Remoxipride (vehicle, 0.7 or 3.5mg/kg) was administered to rats. Endogenous metabolites were analyzed in plasma using a biogenic amine platform and PKPD models were derived for each single metabolite. These models were clustered on basis of proximity between their PKPD parameter estimates, and PKPD models were subsequently fitted for the individual clusters. Finally, the metabolites were evaluated for being significantly affected by remoxipride. In total 44 metabolites were detected in plasma, many of them showing a dose dependent decrease from baseline. We identified 6 different clusters with different time and dose dependent responses and 18 metabolites were revealed as potential biomarker. The glycine, serine and threonine pathway was associated with remoxipride pharmacology, as well as the brain uptake of the dopamine and serotonin precursors. This is the first time that pharmacometabolomics and PKPD modeling were integrated. The resulting PKPD cluster model described diverse pharmacometabolomics responses and provided a further understanding of remoxipride pharmacodynamics. Future research should focus on the simultaneous pharmacometabolomics analysis in brain and plasma to increase the interpretability of these responses.

The influence of drug distribution and drug-target binding on target occupancy: The rate-limiting step approximation.

The influence of drug-target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as "rebinding" or "diffusion-limited binding". This gives rise to a decreased decline of the drug-target complex concentration as a result of a locally higher drug concentration that arises around the target, which leads to prolonged target exposure to the drug. This phenomenon has been approximated by the steady-state approximation, assuming a steady-state concentration around the target. Recently, a rate-limiting step approximation of drug distribution and drug-target binding has been published. However, a comparison between both approaches has not been made so far. In this study, the rate-limiting step approximation has been rewritten into the same mathematical format as the steady-state approximation in order to compare the performance of both approaches for the investigation of the influence of drug-target binding kinetics on target occupancy. While both approximations clearly indicated the importance of kon and high target concentrations, it was shown that the rate-limiting step approximation is more accurate than the steady-state approximation, especially when dissociation is fast compared to association and distribution out of the binding compartment. It is therefore concluded that the new rate-limiting step approximation is to be preferred for assessing the influence of binding kinetics on local target site concentrations and target occupancy.

BMI loci and longitudinal BMI from adolescence to young adulthood in an ethnically diverse cohort.

OBJECTIVE: The association of obesity susceptibility variants with change in body mass index (BMI) across the life course is not well understood. SUBJECTS: In ancestry-stratified models of 5962 European American (EA), 2080 African American (AA) and 1582 Hispanic American (HA) individuals from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we examined associations between 34 obesity single-nucleotide polymorphisms (SNPs) with per year change in BMI, measured by the slope from a growth-curve analysis of two or more BMI measurements between adolescence and young adulthood. For SNPs nominally associated with BMI change (P<0.05), we interrogated age differences within data collection Wave and time differences between age categories that overlapped between Waves. RESULTS: We found SNPs in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 were significantly associated (P<0.0015≈0.05/34) with BMI change in EA and the ancestry-combined meta-analysis. rs9939609 in FTO met genome-wide significance at P<5e-08 in the EA and ancestry-combined analysis, respectively [Beta(se)=0.025(0.004);Beta(se)=0.021(0.003)]. No SNPs were significant after Bonferroni correction in AA or HA, although five SNPs in AA and four SNPs in HA were nominally significant (P<0.05). In EA and the ancestry-combined meta-analysis, rs3817334 near MTCH2 showed larger effects in younger respondents, whereas rs987237 near TFAP2B, showed larger effects in older respondents across all Waves. Differences in effect estimates across time for MTCH2 and TFAP2B are suggestive of either era or cohort effects. CONCLUSION: The observed association between variants in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 with change in BMI from adolescence to young adulthood suggest that the genetic effect of BMI loci varies over time in a complex manner, highlighting the importance of investigating loci influencing obesity risk across the life course.

Brain volume change in first-episode psychosis: an effect of antipsychotic medication independent of BMI change.

OBJECTIVE: The effect of antipsychotic medication on brain structure remains unclear. Given the prevalence of weight gain as a side-effect, body mass index (BMI) change could be a confounder. METHOD: Patients with first-episode psychosis (n = 78) and healthy controls (n = 119) underwent two 1.5T MRI scans with a 1-year follow-up interval. siena (fsl 5.0) was used to measure whole-brain volume change. Weight and height were measured at both time points. Antipsychotic medication use at baseline and follow-up was converted into chlorpromazine equivalent dose and averaged. RESULTS: Patients did not show significantly larger brain volume loss compared with healthy controls. In the whole sample (n = 197), BMI change was negatively associated with brain volume change (ß = -0.19, P = 0.008); there was no interaction effect of group. Among patients, higher antipsychotic medication dosage was associated with greater brain volume loss (ß = -0.45, P < 0.001). This association was not affected by adjusting for BMI change. CONCLUSION: Weight gain was related to brain volume reductions to a similar degree among patients and controls. Antipsychotic dosage-related reductions of brain volume were not confounded by BMI change. Generalizability to contexts involving severe weight gain needs to be established. Furthermore, disentangling effects of medication from illness severity remains a challenge.

Cadmium body burden and increased blood pressure in middle-aged American Indians: the Strong Heart Study.

Cadmium (Cd) is an environmental pollutant that has been associated with cardiovascular disease in populations, but the relationship of Cd with hypertension has been inconsistent. We studied the association between urinary Cd concentrations, a measure of total body burden, and blood pressure in American Indians, a US population with above national average Cd burden. Urinary Cd was measured using inductively coupled plasma mass spectrometry, and adjusted for urinary creatinine concentration. Among 3714 middle-aged American Indian participants of the Strong Heart Study (mean age 56 years, 41% male, 67% ever-smokers, 23% taking antihypertensive medications), urinary Cd ranged from 0.01 to 78.48 µg g-1 creatinine (geometric mean=0.94 µg g-1) and it was correlated with smoking pack-year among ever-smokers (r2=0.16, P<0.0001). Participants who were smokers were on average light-smokers (mean 10.8 pack-years), and urinary Cd was similarly elevated in light- and never-smokers (geometric means of 0.88 µg g-1 creatinine for both categories). Log-transformed urinary Cd was significantly associated with higher systolic blood pressure in models adjusted for age, sex, geographic area, body mass index, smoking (ever vs never, and cumulative pack-years) and kidney function (mean blood pressure difference by lnCd concentration (ß)=1.64, P=0.002). These associations were present among light- and never-smokers (ß=2.03, P=0.002, n=2627), although not significant among never-smokers (ß=1.22, P=0.18, n=1260). Cd was also associated with diastolic blood pressure among light- and never-smokers (ß=0.94, P=0.004). These findings suggest that there is a relationship between Cd body burden and increased blood pressure in American Indians, a population with increased cardiovascular disease risk.

Alcohol use is associated with thinner cerebral cortex and larger ventricles in schizophrenia, bipolar disorder and healthy controls.

BACKGROUND: Excessive alcohol use is associated with brain damage but less is known about brain effects from moderate alcohol use. Previous findings indicate that patients with severe mental illness, particularly schizophrenia, are vulnerable to alcohol-related brain damage. We investigated the association between levels of alcohol consumption and cortical and subcortical brain structures in schizophrenia and bipolar disorder patients and healthy controls, and investigated for group differences for this association. METHOD: 1.5 T structural magnetic resonance images were acquired of 609 alcohol-using participants (165 schizophrenia patients, 172 bipolar disorder patients, 272 healthy controls), mean (s.d.) age 34.2 (9.9) years, 52% men. Past year alcohol use was assessed with the Alcohol Use Disorder Identification Test - Consumption part (AUDIT-C). General linear models were used to investigate associations between AUDIT-C score and cortical thickness, surface area, and total brain and subcortical volumes. RESULTS: Increasing AUDIT-C score was linearly associated with thinner cortex in medial and dorsolateral frontal and parieto-occipital regions, and with larger left lateral ventricle volume. There was no significant interaction between AUDIT-C score and diagnostic group. The findings remained significant after controlling for substance use disorders, antipsychotic medication and illness severity. CONCLUSION: The results show a dose-dependent relationship between alcohol use and thinner cortex and ventricular expansion. The findings are present also at lower levels of alcohol consumption and do not differ between schizophrenia or bipolar disorder patients compared to healthy controls. Our results do not support previous findings of increased vulnerability for alcohol-related brain damage in severe mental illness.

The interaction between physical activity and obesity gene variants in association with BMI: Does the obesogenic environment matter?

Little is known about how obesity susceptibility single nucleotide polymorphisms (SNPs) interact with moderate to vigorous physical activity (MVPA) in relation to BMI during adolescence, once obesogenic neighborhood factors are accounted for. In race stratified models, including European (EA; N=4977), African (AA; N=1726), and Hispanic Americans (HA; N=1270) from the National Longitudinal Study of Adolescent to Adult Health (1996; ages 12-21), we assessed the evidence for a SNPxMVPA interaction with BMI-for-age Z score, once accounting for obesogenic neighborhood factors including physical activity amenities, transportation and recreation infrastructure, poverty and crime. Eight SNPxMVPA interactions with suggestive significance (p<0.10; three in each EA, and AA, two in HA) were observed showing attenuation on BMI-for-age Z score in adolescents with ≥5 versus <5 bouts/week MVPA, except for rs10146997 (near NRXN3). Findings were robust to the inclusion of neighborhood-level variables as covariates. These findings suggest that any attenuation from MVPA on a genetic susceptibility to obesity during adolescence is likely not operating through obesogenic neighborhood factors.